2-Amino-4-pyrimidyl-1,4-dihydropyridine derivatives

ABSTRACT

2-Amino-1,4-dihydropyridines bearing a carbonyl function in the 5-position and being optionally substituted by lower alkyl or phenyl in the 6-position, and the corresponding 2-amino-1,4,5,6,7,8-hexahydro-5-oxoquinolines, which derivatives are further substituted by a carbonyl group in the 3-position and optionally substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3,5-diethyl ester is a representative embodiment, are prepared through condensation of an ylideneacetoacetic acid ester and an amidine.

CROSS REFERENCE

This is a division of Ser. No. 438,603 filed Feb. 1, 1974, now U.S. Pat.No. 3,929,798 which in turn is a division of Ser. No. 336,639, filedFeb. 28, 1973, now U.S. Pat. No. 3,867,393.

DETAILED DESCRIPTION

The present invention pertains to 2-amino-1,4-dihydropyridinederivatives, to processes for their production and use and topharmaceutical compositions containing such compounds and useful asantihypertensive agents and coronary vessel dilators.

In particular, the present invention pertains to compounds of theformula ##STR1## wherein R is hydrogen; lower alkyl; lower alkenyl;lower alkynyl; phenyl; substituted phenyl in which the substituents areone to three members selected from the group consisting of lower alkyl,lower alkoxy, halogeno, nitro, cyano, trifluoromethyl, azido, carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl, loweralkylthio or phenyl; naphthyl; or a heterocyclic ring selected from thegroup consisting of quinolyl, isoquinolyl, pyridyl, pyrimidyl, thenyl,furyl and pyrryl, said heterocyclic ring being unsubstituted orsubstituted by one or two members selected from the group consisting oflower alkyl, lower alkoxy and halogeno;

R¹, when taken independently, is hydrogen, lower alkyl, phenyl orpyridyl;

R², when taken independently, is lower alkyl, lower alkoxy, loweralkoxy(lower) alkoxy), lower alkenyloxy, lower alkynyloxy, amino, loweralkylamino or di(lower alkyl)amino,

R¹ and R² when taken together are alkylene of 2 to 4 carbon atoms; and

R³ is lower alkyl, lower alkoxy, lower alkoxy (lower alkoxy), loweralkenyloxy, lower alkynyloxy, amino, lower alkylamino or di(loweralkyl)amino.

The term lower alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from 1 to 6 carbon atoms. Representative ofsuch lower alkyl groups are thus methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, neopentyl,tert.pentyl, hexyl, and the like.

The term lower alkenyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalethylenic unsaturation as, for example, vinyl, allyl, isopropenyl,2-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl,4-hexenyl, and the like.

The term lower alkynyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalacetylenic unsaturation as, for example, ethynyl, 2-propynyl,4-pentynyl, and the like.

The term lower alkoxy denotes a straight or branched hydrocarbon chainbound to the remainder of the molecule through a ethereal oxygen atomas, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy and hexoxy.

The term lower alkylthio denotes a branched or straight hydrocarbonchain bound to the remainder of the molecule through a divalent sulfuras, for example, methylthio, ethylthio, propylthio, isopropylthio,butylthio, and the like.

The term halogen denotes the substituents fluoro, chloro, bromo andiodo.

As indicated, the present invention also pertains to the physiologicallyacceptable non-toxic acid addition salts of these basic compounds. Suchsalts include those derived from organic and inorganic acids such as,without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methane sulphonic acid, acetic acid, tartaric acid,lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, embonic acid,enanthic acid, and the like.

According to the present invention, the foregoing compounds are preparedby reacting a dicarbonyl compound of the formula: ##STR2## wherein R, R¹and R² are as herein defined, with an amidine of the formula: ##STR3##in which R³ is as herein defined. The condensation proceeds smoothly ingood yields simply by heating the two components, generally in thepresence of an inert organic solvent such as methanol, ethanol, propanoland similar alkanols, ethers such as dioxane and diethyl ehter, glacialacetic acid, pyridine, dimethylformamide, dimethylsulfoxide,acetonitrile and the like. The reaction is conducted at temperatures offrom 20 to 250° C., conveniently at the boiling point of the solvent,and while elevated pressure may be utilized, normal atmospheric pressureis generally satisfactory. The reactants are employed in substantiallyequimolar amounts. The amidine reactant can be employed as the free baseor in the form of a salt such as the hydrohalide salts with the amidinebeing liberated from the salt through treatment with a basic agent suchas an alkali metal alkoxide. The dicarbonyl reagent can be utilized assuch or generated in situ by the reaction of an aldehyde of the formulaRCHO and a β-dicarbonyl compound of the formula R¹ COCH₂ COR².

It is rather surprising that the above described condensation producesthe desired compounds in such good yields and with such high purity forwhile it is known that a benzylideneacetoacetic acid ester can becondensed with an amino crotonic acid ester to yield a1,4-dihydropyridine (Knoevenagel, Ber. 31, 743, 1898), it would beexpected from, for example, Silversmith, J. Org. Chem. 27, 4090 (1952)that the addition of an amidine to an α,β-unsaturated keto compoundwould yield the dihydropyrimidine derivative rather than thedihydropyridine derivative.

Many of the dicarbonyl compounds utilized as one of the reactants areknown to the art and the others can either be generated in situ asherein described or prepared according to methods well known to the art,see for example Org. Reaction XV, 204 et seq. (1967). Typical of thisreactant are the following compounds:

benzylideneacetoacetic acid methyl ester,

ethylideneacetoacetic acid methyl ester,

isopropylideneacetoacetic acid methyl ester,

2-nitrobenzylideneacetoacetic acid methyl ester,

2-nitrobenzylideneacetylacetone,

benzylideneacetylacetone,

3-nitrobenzylidenecacetoacetic acid methyl ester,

3-nitrobenzylideneacetoacetic acid propargyl ester,

3-nitrobenzylideneacetoacetic acid allyl ester,

3-nitrobenzylideneacetoacetic acid β-methoxyethyl ester,

3-nitrobenzylideneacetoacetic acid β-ethoxyethyl ester,

3-nitrobenzylideneacetoacetic acid isopropyl ester,

3-nitrobenzylideneacetylacetone,

4-nitrobenzylideneacetylacetone,

4-nitrobenzylideneacetoacetic acid β-propoxyethyl ester,

4-nitrobenzylideneacetoacetic acid n-propyl ester,

3-nitro-6 -chlorobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid ethyl ester,

2-cyanobenzylidenepropionylacetic acid ethyl ester,

3-cyanobenzylideneacetoacetic acid methyl ester,

3-nitro-4-chlorobenzylideneacetylacetone,

3-nitro-4-chlorobenzylideneacetoacetic acid t-butyl ester,

3-nitro-4-chlorobenzylideneacetoacetic acid methyl ester,

2-nitro-4-methoxybenzylideneacetoacetic acid methyl ester,

2-cyano-4-methylbenzylideneacetoacetic acid ethyl ester,

2-azidobenzylideneacetoacetic acid ethyl ester,

3-azidobenzylideneacetylacetone,

2-methylmercaptobenzylideneacetoacetic acid isopropyl ester,

2-sulphinylmethylbenzylideneacetoacetic acid ethyl ester,

2-sulphonylbenzylidenemethylacetoacetic acid allyl ester,

4-sulphonylmethylbenzylideneacetoacetic acid ethyl ester,

naphth-1-ylideneacetoacetic acid methyl ester,

naphth-1-ylideneacetoacetic acid ethyl ester,

naphth-2-ylideneacetoacetic acid ethyl ester,

2-ethoxynaphth-1-ylideneacetoacetic acid methyl ester,

2-methoxynaphth-1-ylideneacetoacetic acid ethyl ester,

5-bromonaphth-1-ylideneacetoacetic acid methyl ester,

quinol-2-ylmethylideneacetoacetic acid methyl ester,

quinol-3-ylmethylideneacetoacetic acid methyl ester,

quinol-4-ylmethylideneacetoacetic acid ethyl ester,

quinol-8-ylemethylideneacetoacetic acid ethyl ester,

isoquinol-1-ylmethylideneacetoacetic acid methyl ester,

isoquinol-3-ylmethylideneacetoacetic acid methyl ester,

α-pyridylmethylideneacetoacetic acid methyl ester,

α-pyridylmethylideneacetoacetic acid ethyl ester,

α-pyridylmethylideneacetoacetic acid allyl ester,

α-pyridylmethylideneacetoacetic acid cyclohexyl ester,

β-pyridylmethylideneacetoacetic acid β-methoxyethyl ester,

γ-pyridylmethylideneacetoacetic acid methyl ester,

6-methyl-α-pyridylmethylideneacetoacetic acid ethyl ester,

4,6-dimethoxypyrimid-5-ylmethylideneacetoacetic acid ethyl ester,

then-2-ylmethylideneacetoacetic acid ethyl ester,

fur-2-ylmethylideneacetoacetic acid allyl ester,

pyrr-2-ylthylideneacetoacetic acid methyl ester,

nitrobenzylidenepropionylacetic acid ethyl ester,

α-pyridylmethylidenepropionylacetic acid ethyl ester,

α-pyridylmethylidenepropionylacetic acid methyl ester,

α-pyridylmethylideneacetylacetone,

2-, 3- or 4-methoxybenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-methoxybenzylideneacetylacetone,

2-methoxybenzylideneacetoacetic acid allyl ester,

2-methoxybenzylideneacetoacetic acid allyl ester,

2-methoxybenzylideneacetoacetic acid propargyl ester,

2-methoxybenzylideneacetoacetic acid β-methoxyethyl ester,

2-isopropoxybenzylideneacetoacetic acid ethyl ester,

3-butoxybenzylideneacetoacetic acid methyl ester,

3,4,5-trimethoxybenzylideneacetoacetic acid allyl ester,

2-methylbenzylidenepropionylacetic acid methyl ester,

2-, 3- or 4-methylbenzylideneacetoacetic acid ethyl ester,

2-methylbenzylideneacetoacetic acid β-methoxyethyl ester,

2-methylbenzylideneacetoacetic acid β-propoxyethyl ester,

2-methylbenzylideneacetylacetone,

3,4-dimethoxy-5-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-chlorobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-fluorobenzylideneacetoacetic acid ethyl ester,

2-fluorobenzylideneacetoacetic acid methyl ester,

3-chlorobenzylideneacetylacetone,

3-chlorobenzylidenepropionylacetic acid ethyl ester,

3-chlorobenzylideneacetoacetic acid ethyl ester,

2-chlorobenzylideneacetoacetic acid allyl ester,

2-, 3- or 4-trifluoromethylbenzylideneacetoacetic acid isopropyl ester,

3-trifluoromethylbenzylideneacetoacetic acid methyl ester,

2-carbethoxybenzylideneacetoacetic acid ethyl ester,

3-carbomethoxybenzylideneacetoacetic acid methyl ester,

4-carboisopropoxybenzylideneacetoacetic acid isopropyl ester,

4-carbomethoxybenzylideneacetoacetic acid allyl ester,

3-nitrobenzylidenecyclohexane-1,3-dione, and

3-nitrobenzylidenecycloheptane-1,3-dione.

The amidine reactants are similarly known or can be readily producedaccording to known methods, see for example McElvain et al., J.A.C.S.,73, 2760 (1951). Typical of these reactants are the following:

amidinoacetic acid methyl ester,

amidinoacetic acid ethyl ester,

amidinoacetic acid n-propyl ester,

amidinoacetic acid isopropyl ester,

amidinoacetic acid cyclohexyl ester,

amidinoacetic acid β-methoxyethyl ester,

amidinoacetic acid α-ethoxyethyl ester,

amidinoacetic acid β-ethoxyethyl ester,

amidinoacetic acid propargyl ester, and

amidinoacetamide.

As noted above, the compounds of the present invention demonstrate theability to reduce blood pressure and to effect a dilation of thecoronary vessels. They can accordingly be used where either or both ofthese effects are desired. Thus upon parenteral, oral or sublingualadministration, the compounds produce a distinct and long lastingdilation of the coronary vessels which is intensified by a simultaneousnitritelike effect of reducing the load on the heart. The effect onheart metabolism is thus one of energy saving. In addition, thecompounds lower the blood pressure of normotonic and hypertonic animalsand can thus be used as antihypertensive agents. These properties can beconveniently observed in well known laboratory models. Thus for examplethe coronary vessel dilation effect can be observed by measuring theincrease in oxygen saturation in the coronary sinus in the narcotized,heart catheterized dog, as shown in the following table:

    ______________________________________                                                     I.V. Dose                                                                              ΔO.sub.2 %                                                                       Return to normal                               Compound     (mg/kg)  saturation                                                                             O.sub.2 values (hours)                         ______________________________________                                        2-amino-6-methyl-                                                                          0.02     33       2.5                                            4-(2-nitrophenyl)-                                                            1,4-dihydropyri-                                                              dine-3,5-dicarboxy-                                                           lic acid 3-ethyl-5-                                                           methyl ester                                                                  2-amino-6-methyl-                                                                          0.03     32       3                                              4-(2-cyanophenyl)-                                                            1,4-dihydropyri-                                                              dine-3,5-dicarbox-                                                            ylic acid diethyl                                                             ester                                                                         2-amino-6-methyl-                                                                          0.01     23       2                                              4-(3-nitrophenyl)-                                                            1,4-dihydropyri-                                                              dine-3,5-dicarbox-                                                            ylic acid diethyl                                                             ester                                                                         ______________________________________                                    

The hypotensive activity of the present compounds can be observed bymeasuring the blood pessure of hypertensive rates followingadministration of the compounds. The following table demonstrates thedose which results in at least a 15 mm Hg reduction in blood pressure ofsuch animals:

    ______________________________________                                        Compound              Dose (mg/kg)                                            ______________________________________                                        2-amino-6-methyl-4-phenyl-1,4-                                                                      1.0                                                     dihydropyridine-3,5-dicarboxylic                                              acid diethyl ester                                                            2-amino-6-methyl-4-(2-nitrophenyl)-                                                                 0.1                                                     1,4-dihydropyridine-3,5-dicarboxylic                                          acid 3-ethyl ester 5-methyl ester                                             2-amino-6-methyl-4-(2-methoxyphenyl)-                                                               1.0                                                     1,4-dihydropyridine-3,5-dicarboxylic                                          acid diethyl ester                                                            2-amino-6-methyl-4-(2-cyanophenyl)-1,4-                                                             1.0                                                     dihydropyridine-3,5-dicarboxylic acid                                         diethyl ester                                                                 2-amino-6-methyl-4-(2-trifluoromethyl-                                                              1.0                                                     phenyl)-1,4-dihydropyridine-3,5-dicar-                                        boxylic acid diethyl ester                                                    2-amino-6-methyl-4-(3-nitrophenyl)-1,4-                                                             1.0                                                     dihydropyridine-3,5-dicarboxylic acid                                         diethyl ester                                                                 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-                                                             1.0                                                     dihydropyridine-3,5-dicarboxylic acid                                         3-ethyl ester 5-methyl ester                                                  2-amino-6-methyl-4-(3-nitrophenyl)-1,4-                                                             1.0                                                     dihydropyridine-3,5-dicarboxylic acid                                         3-ethyl ester 5-β-methoxyethyl ester                                     2-amino-5-acetyl-6-methyl-4-(3-nitro-                                                               3.1                                                     phenyl)-1,4-dihydropyridine-3-carbox-                                         ylic acid ethyl ester                                                         2-amino-6-methyl-4-(3-nitro-6-chloro-                                                               1.0                                                     phenyl)-1,4-dihydropyridine-3,5-dicarb-                                       oxylic acid 3-ethyl ester 5-methyl ester                                      ______________________________________                                    

The toxicity of the compounds is remarkably low. Thus for example thetoxic dose of 2-amino-6-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethylester in mice upon oral administration is greater than 1000 mg/kg.

In addition to the effect on blood pressure and coronary vessels, thecompounds also lower the excitability of the stimulus formation andexcitation conduction system within the heart so that anantifibrillation action is observed at therapeutic doses. The tone ofthe smooth muscle of the vessels is also greatly reduced. Thisvascular-spasmolytic action can be observed in the entire vascularsystem as well as in more or less isolated and circumscribed vascularregions such as the central nervous system. In addition, a strongmuscular-spasmolytic action is manifested in the smooth muscle of thestomach, the intestinal tract, the urogenital tract and the respiratorysystem. Finally, there is some evidence that the compounds influence thecholesterol level and lipid level of the blood. These effects complementone another and the compounds are thus highly desirable aspharmaceutical agents to be used in the treatment of hypertension andconditions characterized by a constriction of the coronary bloodvessels.

Pharmaceutical compositions for effecting such treatment will contain amajor or minor amount, e.g. from 95 to 0.5%, of at least one2-amino-1,4-dihydropyridine as herein defined in combination with apharmaceutical carrier, the carrier comprising one or more solid,semi-solid or liquid diluent, filler and formulation adjuvant which isnontoxic, inert and pharmaceutically acceptable. Such pharmaceuticalcompositions are preferably in dosage unit form; i.e. physicallydiscrete units containing a predetermined amount of the drugcorresponding to a fraction or multiple of the dose which is calculatedto produce the desired therapeutic response. The dosage units cancontain one, two, three four or more single doses or, alternatively,one-half, third or forth of a single dose. A single dose preferablycontains an amount sufficient to produce the desired therapeutic effectupon administration at one application of one or more dosage unitsaccording to a predetermined dosage regimen, usually a whole, half,third or quarter of the daily dosage administered once, twice, three offour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the daily dose will befrom about 0.001 to about 2 mg/kg, preferably 0.005 to 1.0 mg/kg, whenadministered parenterally and from about 0.1 to about 20 mg/kg,preferably 0.5 to 10 mg/kg, when administered orally. In some instancesa sufficient therapeutic effect can be obtained at lower doses while inothers, larger doses will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powers are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulatd for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As a alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themidicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that given quantity contains a predetermined amountof the compound. Syrups can be prepared by dissolving the compound in asuitably flavored aqueous sucrose solution while elixirs are preparedthrough the use of a nontoxic alcoholic vehicle. Suspensions can beformulated by dispersing the compound in a nontoxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxyethylene sorbitol esters, preservatives, flavor additives such aspeppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral adminstration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

The following examples will serve to further typify the nature of thepresent invention through the presentation of specific embodiments.These examples should not be construed as a limitation on the scope ofApplicants' invention since the subject matter regarded as the inventionis set forth in the appended claims.

EXAMPLE 1

Upon boiling a solution of 21.8 g of benzylideneacetoacetic acid ethylester and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanolfor 2 hours, 2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl esterof melting point 164° C. (alcohol) is obtained.

Yield: 67% of theory.

EXAMPLE 2

Upon boiling a solution of 24.9 g of 2-nitrobenzylideneacetoacetic acidmethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 100 ml ofethanol for 1 hour, 2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl ester 5-methyl ester of melting point 168° C. (alcohol) isobtained.

Yield: 59% of theory.

EXAMPLE 3

Upon boiling a solution of 24.8 g of 2-methoxybenzylideneacetoaceticacid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 150 mlof ethanol for 1 hour,2-amino-6-methyl-4-(2-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 170° C. (ethanol) isobtained.

Yield: 65% of theory.

EXAMPLE 4

Upon boiling a solution of 23.2 g of 2-methylbenzylideneacetoacetic acidethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 150 ml ofethanol for 2 hours, 2-amino-6-methyl-4-(2-methylphenyl)-1,4-dihydropyridine-3,5 -dicarboxylic aciddiethyl ester of metling point 130° C. (ethanol) is obtained.

Yield: 71% of theory.

EXAMPLE 5

Upon boiling a solution of 24.3 g of 2-cyanobenzylideneacetoacetic acidethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 100 ml ofethanol for 2 hours, 2-amino-6 -methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl esterof melting point 208° C. (ethanol) is obtained.

Yield: 54% of theory.

EXAMPLE 6

Upon boiling a solution of 14.2 g of2-trifluoromethylbenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour,2-amino-6-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 156° C. (ethanol)is obtained.

Yield: 76% of theory.

EXAMPLE 7

Upon boiling a solution of 12.6 g of 3-chlorobenzylideneacetoacetic acidethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofethanol for 2 hours, 2-amino-6-methyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point 157- 159° C. (ethanol) is obtained.

Yield: 62% of theory.

EXAMPLE 8

Upon boiling a solution of 13.2 g of4-methylmercaptobenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour, 2-amino-6-methyl-4-(4-methylmercaptophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 165° C. (ethylacetate/petroleum ether) is obtained.

Yield: 49% of theory.

EXAMPLE 9

Upon boiling a solution of 26.3 g of 3-nitrobenzylideneacetoacetic acidethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 200 ml ofethanol for 1 hour, 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine 3,5-dicarboxylic aciddiethyl ester of melting point 169° C. (ethanol) is obtained.

Yield: 58% of theory.

EXAMPLE 10

Upon boiling a solution of 24.9 g of 3-nitrobenzylideneacetoacetic acidmethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 180 ml ofethanol for 1 hour, 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl ester 5-methyl ester of melting point 124° C. is obtained.

Yield: 59% of theory.

EXAMPLE 11

Upon heating a solution of 13.8 g of 3-nitrobenzylideneacetoacetic acidisopropyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150 ml ofethanol for 2 hours, 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl 5-isopropyl ester of melting point 206- 207° C. (alcohol) isobtained.

Yield: 62% of theory.

EXAMPLE 12

Boiling a solution of 10.9 g of 3-nitrobenzylideneacetoacetic acidpropargyl ester and 5.2 g of amidinoacetic acid ethyl ester in 100 ml ofethanol for 1 hour yields 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylicacid 3-ethyl ester 5-propargyl ester of melting point 181° C. (ethanol).

Yield: 59% of theory.

EXAMPLE 13

Heating a solution of 14.6 g of 3-nitrobenzylideneacetoacetic acidβ-methoxyethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150ml of ethanol for 1 hour yields2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylicacid 3-ethyl ester 5β-methoxyethyl ester of melting point 179° C. (ethylacetate/petroleum ether).

Yield: 58% of theory.

EXAMPLE 14

Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 5.0 g ofacetylacetone and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofethanol for 2 hours, 2-amino-5-acetyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid ethylester of melting point 217° C. (ethanol) is obtained.

Yield: 48% of theory.

EXAMPLE 15

Upon boiling a solution of 14.2 g of 3-nitro-6-chlorobenzylideneacetoacetic acid methyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour,2-amino-6-methyl-4-(3-nitro-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester of melting point 124°C. (ethanol) is obtained.

Yield: 73% of theory.

EXAMPLE 16

Upon boiling a solution of 10.4 g of 2-furfurylideneacetoacetic acidethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofethanol for 2 hours, 2-amino-6-methyl-4-(fur-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester ofmelting point 183° C. (isopropanol) is obtained.

Yield: 78% of theory.

EXAMPLE 17

Upon boiling a solution of 14.0 g of benzylidene-benzoylacetic acidethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150 ml ofethanol for 2 hours, 2-amino-4,6-diphenyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester ofmelting point 183° C. (ethanol) is obtained.

Yield: 48% of theory.

EXAMPLE 18

Upon heating a solution of 15.6 g of ethylideneacetoacetic acid ethylester and 13.0 g of amidinoacetic acid ethyl ester in 100 ml of ethanolfor 2 hours, 2-amino-4,6-dimethyl- 1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 140° C. (isopropanol) is obtained.

Yield: 59% of theory.

EXAMPLE 19

Upon boiling a solution of 2.8 g of acetaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 2 hours, 2-amino-4-methyl-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 236° C. (ethanol) is obtained.

Yield: 53% of theory.

EXAMPLE 20

Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester for 1hour, 2-amino-4-(3-nitrophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of meltingpoint > 260° C. is obtained (alcohol/DMF).

Yield: 61% of theory.

EXAMPLE 21

Upon boiling a solution of 7.1 g of 3-chlorobenzaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 150ml of ethanol for 2 hours, 2-amino-4-(3-chlorophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 266° C. (ethanol/DMF) isobtained.

Yield: 66% of theory.

EXAMPLE 22

Upon boiling a solution of 5.3 g of pyridin-2 -aldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 150ml of alcohol for 3 hours,2-amino-4-(α-pyridyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3 -carboxylicacid ethyl ester of melting point 260° C. is obtained (alcohol).

Yield: 46% of theory.

EXAMPLE 23

Upon heating a solution of 7.6 g of 2-nitrobenzaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 2 hours,2-amino-4-(2-nitrophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 212° C. (alcohol) isobtained.

Yield: 69% of theory.

EXAMPLE 24

Upon heating a solution of 7.9 g of quinolin-4-aldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 150ml of ethanol for 3 hours,2-amino-4-(quinol-4-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinolinecarboxylicacid 3-ethyl ester of melting point >260 C. (ethanol/DMF) is obtained.

Yield: 81% of theory.

EXAMPLE 25

Upon boiling a solution of 5.7 g of 4,6-dimethoxypyrimidin- 5-aldehyde,3.8 g of cyclohexane-1,3-dione and 4.4 g of amidinoacetic acid ethylester in 80 ml of ethanol for 8 hours,2-amino-4-(4,6-dimethoxypyrimid-5-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of meltingpoint 273° C. (alcohol) is obtained.

Yield: 65% of theory.

EXAMPLE 26

Upon boiling a solution of 6.3 g of 1-naphthaldehyde, 4.5 g ofcyclohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in 150ml of ethanol for 2 hours, 2-amino-4-(naphth-1-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acidethyl ester of melting point 279° C. (ethanol/DMF) is obtained.

Yield: 64% of theory.

EXAMPLE 27

Upon heating a solution of 6.3 g of isoquinolin-1 -aldehyde, 4.5 g ofcyclohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 2 hours, 2-amino-4-(isoquinol-1-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 272° C. (ethanol) isobtained.

EXAMPLE 28

Upon heating a solution of 4.8 g of 6-methylpyridin- 2-aldehyde, 4.5 gof cyclohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in120 ml of ethanol for 8 hours, 2-amino-4-(6-methylpyrid-2-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point > 260 C. (ethanol/DMF)is obtained.

Yield: 46% of theory.

EXAMPLE 29

Upon boiling a solution of 13.3 g of 3-nitrobenzylideneacetoacetic acidethyl ester and 5.1 g of amidinoacetamide in 150 ml of ethanol for 2hours, 2-amino-6-methyl-5-carbethoxy-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid amide of meltingpoint > 260° C. (alcohol) is obtained.

Yield: 52% of theory.

EXAMPLE 30

Upon heating a solution of 6.5 g of 2-cyanobenzaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 5 hours, 2-amino-4-(2-cyanophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 165° C. (ethanol) is obtained.

Yield: 49% of theory.

EXAMPLE 31

Upon heating a solution of 26.3 g of 3-nitrobenzylideneacetoacetic acidethyl ester and 14.4 g of amidinoacetic acid isopropyl ester in 250 mlof ethanol for 2 hours, 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-isopropyl ester 5-ethyl ester of melting point 175-6° C. (ethanol) isobtained.

Yield: 77% of theory.

EXAMPLE 32

Heating a solution of 14.3 g of 2-trifluoromethylbenzylideneacetoaceticacid ethyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 150ml of ethanol for 1 hour yields2-amino-6-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 5-ethyl ester of melting point106° C.

Yield: 49% of theory.

EXAMPLE 33

Upon heating a solution of 13.9 g of 3-nitrobenzylideneacetoacetic acidisopropyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 180ml of ethanol for 1 hour,2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diisopropyl ester of melting point 122° C. (ether) is obtained.

Yield: 62% of theory.

EXAMPLE 34

Upon boiling a solution of 12.2 g of 2-cyanobenzylideneacetoacetic acidethyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 200 ml ofethanol for 1 hour,2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl esrter 5-ethyl ester of melting point 200° C.(isopropanol) is obtained.

Yield: 58% of theory.

EXAMPLE 35

Upon heating a solution of 12.5 g of 3-nitrobenzylideneacetoacetic acidmethyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 150 mlof ethanol for 2 hours, 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-isopropyl ester 5-methyl ester of melting point 167° C. (ethanol) isobtained.

Yield: 82% of theory.

EXAMPLE 36

Upon heating a solution of 11.0 g of 2-trifluoromethyl-4-nitrobenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g ofamidinoacetic acid ethyl ester in 250 ml of ethanol of 2 hours,2-amino-4-(2-trifluoromethyl-4-nitrophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 264° C. (ethanol) is obtained.

Yield: 62% of theory.

EXAMPLE 37

Heating a solution of 13.2 g of 3-nitrobenzylideneacetoacetic acid ethylester and 7.2 g of amidinoacetic acid n-propyl ester in 200 ml ofethanol for 2 hours yields 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-n-propyl ester 5-ethyl ester of melting point 168° C. (ethanol).

Yield: 79% of theory.

EXAMPLE 38

Boiling a solution of 8.5 g of 6-nitroveratraldehyde, 4.0 g ofcyclohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in 150ml of ethanol for 1 hour yields 2-amino-4-(2-nitro-4,5-dimethoxyphenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 261° C. (ethanol).

Yield: 52% of theory.

EXAMPLE 39

Boiling a solution of 13.2 g of 3-nitrobenzylideneacetoacetic acid ethylester and 8.0 g of amidinoacetic acid β-methoxyethyl ester in 200 ml ofethanol for 2 hours yields2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylicacid 3-(β-methoxyethyl) ester 5-ethyl ester of melting point 174° C.

Yield: 59% of theory.

EXAMPLE 40

Upon heating a solution of 6.1 g of biphenyl-2 -aldehyde, 3.8 g ofcyclohexane-1,3-dione and 5.1 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 1 hour, 2-amino-4-(biphenyl-2-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 248° C. (ethanol) isobtained.

Yield: 45% of theory.

EXAMPLE 41

Boiling a solution of 13.4 g of (1-naphthylidene)acetoacetic acid ethylester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanolfor 8 hours yields 2-amino-6-methyl-4-(1-naphthyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point 174° C. (ethanol).

Yield: 62% of theory.

EXAMPLE 42

Upon heating a solution of 11.5 g of 2-cyanobenzyli-deneacetoacetic acidmethyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 100 mlof ethanol for 6 hours,2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-methyl ester of melting point 211° C. (ethanol)is obtained. Yield: 72% of theory.

EXAMPLE 43

Upon boiling a solution of 11.5 g of 2-cyonobenzylideneacetoacetic acidmethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofethanol for 8 hours,2-amino-6-methyl-4-(2-cyanophenyl-)-1,4-dihydropyridine-3,5-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5-methyl ester of melting point 224° C. (ethanol) isobtained. Yield: 66% of theory.

EXAMPLE 44

Upon boiling a solution of 14.8 g of 2-phenylbenzylideneacetoacetic acidethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofethanol for 8 hours, 2-amino-6-methyl-4-(biphenyl-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester of melting point182° C. (ethanol) is obtained. Yield: 41% of theory.

EXAMPLE 45

Upon heating a solution of 12.5 g of 3-nitrobenzylideneacetoacetic acidmethyl ester and 7.2 g of amidinoacetic acid n-propyl ester in 100 ml ofethanol for 6 hours,2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylicacid 3-n-propyl ester 5-methyl ester of melting point 155° C. (ethanol)is obtained. Yield: 69% of theory.

EXAMPLE 46

Upon heating a solution of 12.2 g of (2-thenylidene)-acetoacetic acidethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofethanol for 4 hours,2-amino-6-methyl-4-(2thenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point 170° C. (ethanol) is obtained. Yield: 73%of theory.

EXAMPLE 47

Upon heating a solution of 10.9 g of benzylideneacetoacetic aciddiemethylamide and 5.0 g of amidinoacetamide in 100 ml of ethanol for 8hours,2-amino-6-methyl-4-phenyl-5-(N,N-dimethylaminocarbonyl)-1,4-dihydropyridine-3-carboxylicacid amide of melting point 236° C. (ethanol) is obtained. Yield: 50% oftheory.

EXAMPLE 48

Heating a solution of 10.9 g of benzylideneacetoacetic aciddimethylamide and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofmethanol for 6 hours yields2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl ester 5-(N,N-dimethylamide) of melting point 230° C. (alcohol).Yield: 61% of theory.

EXAMPLE 49

Boiling a solution of 13.2 g of 2-nitrobenzylideneacetoacetic acid ethylester and 7.2 g of amidinoacetic acid isopropyl ester in 100 ml ofethanol for 6 hours yields2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-ethyl ester of melting pont 139° C.(isopropanol). Yield: 39% of theory.

EXAMPLE 50

Boiling a solution of 13.2 g of 2-nitrobenzylideneacetoacetic acid ethylester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanolfor 6 hours yields2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 159° C. (ethanol). Yield: 52% oftheory.

EXAMPLE 51

Upon heating a solution of 12.5 g of 2-nitrobenzylideneacetoacetic acidmethyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 100 mlof ethanol for 8 hours, 2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropylester 5-methyl ester of melting point 203° C. (isopropanol) is obtained.Yield: 50% of theory.

EXAMPLE 52

Upon heating a solution of 12.2 g of 2-cyanobenzylideneacetoacetic acidethyl ester and 7.2 g of amidinoacetic acid n-propyl ester in 100 ml ofethanol for 8 hours,2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-ester of melting point 182° C. (ethanol) isobtained. Yield: 62% of theory.

EXAMPLE 53

Upon heating a solution of 13.9 g of 3-nitrobenzylideneacetoacetic acidisopropyl ester and 7.2 g of amidinoacetic acid n-propyl ester in 100 mlof ethanol for 6 hours,2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-isopropyl ester of melting point 199° C.(isopropanol) is obtained. Yield: 75% of theory.

EXAMPLE 54

Heating a solution of 6.5 g of 3-cyanobenzaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 6 hours yields 2-amino-4-(3-cyanophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acidethyl ester of melting point 262° C. (ethanol/dimethylformamide). Yield:56% of theory.

EXAMPLE 55

Upon heating a solution of 9.3 g of 3-bromobenzaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 8 hours,2-amino-4-(3-bromophenyl-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylicacid ethyl ester of melting point 255° C. (ethanol) is obtained. Yield:44% of theory.

EXAMPLE 56

Upon boiling a solution of 9.3 g of 2-bromobenzaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 6 hours.2-amino-4-(2-bromophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylicacid ethyl ester of melting point 245° C. (ethanol) is obtained. Yield:46% of theory.

EXAMPLE 57

Upon heating a solution of 8.9 g of 3-carbethoxybenzaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 4 hours,2-amino-4-(3-carbethoxyphenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylicacid ethyl ester of melting point 234° C. (ethanol) is obtained. Yield:54% of theory.

EXAMPLE 58

Upon heating a solution of 7.4 of 2-azidobenzaldehyde, 5.6 g ofcyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 4 hours,2-amino-4-(2-azidophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylicacid ethyl ester of melting point 209° C. (ethanol) is obtained. Yield:58% of theory.

We claim:
 1. A compound of the formula: ##STR4## wherein R is pyrimidyl,unsubstituted or substituted by one or two members selected from thegroup consisting of lower alkyl, lower alkoxy and halogeno; andR³ islower alkoxy or lower alkoxy (lower alkoxy).
 2. The compound accordingto claim 1 which is2-amino-4-(4,6-dimethoxypyrimid-5-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylicacid ethyl ester.
 3. The method of effecting coronary vessel dilationand a reduction in blood pressure in an animal which comprisesadministering thereto an effective amount of a compound according toclaim
 1. 4. A pharmaceutical composition for use in effecting coronaryvessel dilation and a reduction in blood pressure which comprises aneffective amount of a compound according to claim 1 and a pharmaceuticalcarrier.